The present invention, in some embodiments thereof, relates to antibodies targeted against lysyl-oxidase like protein-2 (LOXL-2) which are capable of altering the architecture of pathologocial collagen assembly.
The extracellular matrix (ECM) is an essential mediator of tissue function that provides both chemical and mechanical stimuli to influence cellular behavior in both health and disease. The ECM consists of a mesh of fibrillar and non-fibrillar collagens, elastic fibers, glycoproteins and proteoglycans that assemble into complex networks in a tissue specific manner which determine the biophysical properties of tissues such as stiffness, compliance and resilience. Remodeling of the ECM by a variety of tissue remodeling enzymes that cross-link, glycosylate and/or degrade the ECM, can create space for cells to migrate, regulate tissue architecture, and activate, deactivate, or alter the activity of signaling molecules. Tightly controlled ECM homeostasis is therefore essential for life, and dysregulated ECM remodeling can result with pathologic outcomes such as cancer and fibrosis. Indeed, over-expression of tissue remodeling enzymes is one of the hallmarks of cancer and examination of ECM derived from solid tumors reveals massive deposition of collagen, altered ECM morphology and increased tissue stiffness. In addition, proteomic analyses have demonstrated that the composition of the tumor extracellular matrix changes with tumor metastatic potential. Thus, controlling ECM morphology and composition is considered as potent therapeutic strategy for cancer patients (Siddikuzzaman, Grace, V. M. & Guruvayoorappan, C. Inflammopharmacology 19, 117-29 (2011). However, despite the growing amount of data correlating between ECM biophysical properties and tumor malignancy, how to clinically interfere with the altered biophysical ECM during the onset and progression of cancer is unknown.
The lysyl oxidases (LOX) comprise a family of five copper-dependent amine oxidases homologs enzymes (LOX and LOXL1-4) that initiate the process of covalent intra- and intermolecular cross-linking of collagens and elastin. Among the LOX family, LOX and LOXL2 are highly expressed in many human cancers, partly and adversely in correlation to clinical outcome. Activation of LOX family members during cancer has been demonstrated to increase the stiffness of the tissue due to extensive crosslinking of collagen fibrils and to effect downstream signals by modification of snail and integrins, repression of E-cadherin leading to induction of epithelial to mesenchymal (EMT) transition. Interestingly, LOXL2 is highly over-expressed mainly in invasive metastatic tumors more than noninvasive tumors, and is linked to promoting tumor cell invasion, angiogenesis and remodeling of the tumor microenvironment. LOXL2 has been proposed to function both extracellularly and intracellularly to activate oncogenic signaling pathways leading to epithelial-mesenchymal transition (EMT) by and invasion of breast cancer cells. In the tumor stroma, LOXL2 mediates fibroblast activation through integrin engagement and FAK signaling. It has been recently shown that LOXL2 and the transcription factor, E47, contribute to early steps of metastatic colonization by cell and noncell autonomous functions regulating the recruitment of bone marrow progenitor cells to the lungs and by direct transcriptional regulation of fibronectin and cytokines TNFα, ANG-1 and GM-CSF. Genetic, chemical or antibody inhibition of LOXL2 significantly reduced lungs, liver and bone metastasis through its effect on matrix remodeling and cell invasion (Barker, H. E. et al. Cancer Res 71, 1561-72 (2011); Barry-Hamilton, V. et al. Nat Med 16, 1009-17 (2010)).
An antibody developed to specifically target the fourth SRCR domain of LOXL-2 is disclosed in Barry-Hamilton V. et al., Nat Med. 2010 September; 16(9):1009-17.
An antibody targeted to the catalytic site of LOXL-2 is disclosed in U.S. Pat. No. 8,168,180.